When Friend Erytroleukemia cells (FELC) are exposed to a variety of chemical agents capable of inducing terminal differentiation their DNA undergoes a genome-wide demethylation in the absence of DNA replication. Considerable evidence has accumulated to indicate that demethylation of specific genes, or of portion of specific regions of the DNA, is correlated with gene expression. The transient genome-wide demethylation observed during FELC differentiation must be an expression of the fact that the overall pattern of DNA methylation changes during differentiation with some genes becoming active in transcription and others becoming silent. The mechanism of DNA demethylation is completely unknown: theoretically, inhibition during at least two cycles of DNA replication of maintenance methylase, an enzyme capable of methylating hemimethylated DNA, could result in DNA demethylation and changes in the DNA methylation pattern. However, the inhibition of maintenance methylase can not be involved in the genome wide, transient demethylation that is observed in the early phases of FELC differentiation, since this occurs in the absence of DNA duplication.